The main objective of this proposal is the development of effective agents for the prevention of chemical carcinogenesis. Proteases are induced by promoting agents such as phorbol myristate acetate, and the action of this tumor promoter is inhibited by protease inhibitors. Protease inhibitors also delay the appearance of skin tumors by the complete carcinogen dibenzanthrene. Thus, protease inhibitors may be useful as preventive agents in a variety of carcinogenic systems. We will test the effect of protease inhibitors in vivo in three systems: Initiation and promotion of mouse skin tumors; acetyl- aminofluorene liver cancer in rats; and bladder cancer in rats fed FANFT. The effect of protease inhibitors on the growth of normal and transformed cells in culture will also be studied. An additional objective is the elucidation of the role of proteases in the mechanism of carcinogenesis and the relationship between proteases and cyclic AMP. Proteases may cause modification of the cell membrane for uncontrolled growth, perhaps by lowering the cyclic AMP level. We will study proteases (including serum protease and plasminogen levels) and cAMP levels in animals undergoing chemical carcinogenesis. Non-toxic protease inhibitors, e.g. e-aminocaproic acid and Leupeptin, will be looked for as preventive agents applicable to man.